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1999 Fiscal Year Final Research Report Summary

Relationship between intracellular traffic of proteins containing expanded polyglutamine, aggregate formation, and cell death

Research Project

Project/Area Number 10470156
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionInternational University of Health and Welfare (1999)
Jichi Medical University (1998)

Principal Investigator

NISHIZAWA Masatoyo  International University of Health and Welfare, Department of Health Science, Professor, 保健学部, 教授 (80198457)

Co-Investigator(Kenkyū-buntansha) TAKIYAMA Yoshihisa  Jichi Medical School, Department of Neurology, Instructor, 保健学部, 講師 (00245052)
Project Period (FY) 1998 – 1999
KeywordsCAG repeat / polyglutamine / aggregate formation / neuronal cell death / microtubulus organizing center
Research Abstract

In order to elucidate the mechanism of selective neuronal cell death in polyglutamine diseases caused by abnormal expansion of CAG repeat units, various constructs expressing part of ataxin-3, the product of the disease-causing gene MJD 1 of Machado-Joseph disease, as fusion protein with GFP, were introduced to COS cells, and subcellular localization of expressed ataxin-3 fragments was analyzed under fluorescence microscopy.
We found that the C-terminal end of ataxin-3 is essential to formation of cytoplasmic aggregates. These cytoplasmic aggregates were surrounding the nucleus and formed mostly in the juxtanuclear region. Confocal laser microscopy revealed that these aggregates were co-localized with tubulin, and especially, juxtanuclear aggregates were co-localized with gamma-tubulin, which is now known as a marker of microtubulus organizing center (MTOC). These results indicate that the C-terminal portion of ataxin-3 can interact with tubulins, and the aggregates formed by expanded polyglutamine and the C-terminal region, accumulate in the MTOCs.
The N-terminal region flanking the polyglutamine tract of ataxin-3 contained active sequence of nuclear localization signal and also a region with coiled-coil conformation. The latter region was found to be invloved in the aggregates formed by expanded polyglutamine. Overexpression of the construct expressing the latter region resulted in the reduction of intranuclear aggregates formed by expanded polyglutamine derived from DRPLA protein and subsequent cell death.
Our present study indicates the important role of intramolecular domains of the products of disease-causig genes in the formation of cytoplasmic and intranuclear aggregates.

  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Takiyama Y, et al: "Maternal anticipation in Machado-Joseph disease(MJD): some familial factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family."J. Neurol. Sci.. 155. 141-145 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takiyama Y, et al: "A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded GAG repeat in the SCA6/CACN1A4 gene"J. Neurol Sci. 158. 141-147 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takano, H et al: "Close associations between the prevalence rates of dominantly inherited spinocereballar ataxias with CAG repeat expansion and the frequencies of large normal CAG alleles in Japanese and Caucasian populations,"Am. J. Hum. Genet.. 63. 1060-1066 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takiyama Y, et al: "Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy(DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases."Hum Mol. Genet. 8. 453-457 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takiyama Y, Shimazaki H, Morita M, Soutome M, Sakoe K, Esumi E, Yoshida M, Igarashi S, Tanaka H, Tsuji S, Sasaki H, Wakisaka A, Nakano I, Nishizawa M: "Maternal anticipation in Machado-Joseph disease (MJD): some familial factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family."J Neurol Sci. 155. 141-145 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takiyama Y, Sakoe K, Namekawa M, Soutome M, Esumi E, Ogawa T, Ishikawa K, Mizusawa H, Nakano I, Nishizawa M: "A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene."J Neurol Sci. 158. 141-147 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takano H, Cancel 0, Ikeuchi T, Lorenzetti D, Mawad R, Stevanin 0, Didierjean 0, Durr A, Oyake M, Shimohata T, Sasaki R, Koide R, Igarashi S, Hayashi S, Takiyama Y, Nishizawa M, Tanaka H, Zoghbi H, Brice A, Tsuji S: "Close associations between the prevalence rates of dominantly inherited spinocerebellar ataxias with CAG repeat expansions and the frequencies of large normal CAG alleles in Japanese and Caucasian populations."Am I Hum Genet. 63. 1060-1066 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takiyama Y, Sakoe K, Amaike M, Soutome M, Ogawa T, Nakano I, Nishizawa M: "Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases."Hum Mol Genet. 8. 453-457 (1999)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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